Imbalance of the intestinal virome and altered viral-bacterial interactions caused by a conditional deletion of the vitamin D receptor

Abstract

Vitamin D receptor (VDR) deficiency is associated with cancer, infection, and chronic inflammation. Prior research has demonstrated VDR regulation of bacteria; however, little is known regarding VDR and viruses. We hypothesize that VDR deficiency impacts on the intestinal virome and viral-bacterial interactions. We specifically deleted VDR from intestinal epithelial cells (VDR ΔIEC ), Paneth cells (VDR ΔPC ), and myeloid cells (VDR ΔLyz ) in mice. Feces were collected for shotgun metagenomic sequencing and metabolite profiling. To test the functional changes, we evaluated pattern recognition receptors (PRRs) and analyzed microbial metabolites. Vibrio phages, Lactobacillus phages, and Escherichia coli typing phages were significantly enriched in all three conditional VDR-knockout mice. In the VDR ΔLyz mice, the levels of eight more virus species (2 enriched, 6 depleted) were significantly changed. Altered virus species were primarily observed in female VDR ΔLyz (2 enriched, 3 depleted) versus male VDR ΔLyz (1 enriched, 1 depleted). Altered alpha and beta diversity (family to species) were found in VDR ΔLyz . In VDR ΔIEC mice, bovine viral diarrhea virus 1 was significantly enriched. A significant correlation between viral and bacterial alterations was found in conditional VDR knockout mice. There was a positive correlation between Vibrio phage JSF5 and Cutibacterium acnes in VDR ΔPC and VDR ΔLyz mice. Also, there were more altered viral species in female conditional VDR knockout mice. Notably, there were significant changes in PRRs: upregulated TLR3, TLR7, and NOD2 in VDR ΔLyz mice and increased CLEC4L expression in VDR ΔIEC and VDR ΔPC mice. Furthermore, we identified metabolites related to virus infection: decreased glucose in VDR ΔIEC mice, increased ribulose/xylulose and xylose in VDR ΔLyz mice, and increased long-chain fatty acids in VDR ΔIEC and VDR ΔLyz female mice. Tissue-specific deletion of VDR changes the virome and functionally changes viral receptors, which leads to dysbiosis, metabolic dysfunction, and infection risk. This study helps to elucidate VDR regulating the virome in a tissue-specific and sex-specific manner.

Extraintestinal roles of intestinal vitamin D receptor in protecting against dysbiosis and tumorigenesis in breast cancer

“…Our studies support the critical role of VDR in maintaining intestinal and microbial homeostasis [9][10][11] . We established the first conditional deletion of intestinal epithelial VDR mouse model (VDR ΔIEC ) and demonstrated that intestinal bacterial abundance and function are significantly altered in VDR ΔIEC mice 7,12 .…”

Bacterial and Viral Co-Infection in the Intestine: Competition Scenario and Their Effect on Host Immunity

“…By constructing knockout mice with specific deletion of VDR in IECs (VDR∆IEC), Paneth cells (VDR∆PC) and myeloid cells (VDR∆Lyz), Jilei Zhang et al analyzed the bacterial and viral composition and metabolites of each group of mice and found that tissue-specific deletion of VDR altered the viral population and functionally changed the viral receptor, which resulted in ecological dysregulation, metabolic dysfunction, and infection risk. Expression of TLR3/7, NOD1/2, and NLR6 was upregulated in knockout mice, and C-type lectin receptor 4L (CLR4L) was significantly upregulated (Figure 2) [93]. Overall, the significant alterations in pattern recognition receptors (PRRs) of conditional VDR knockout mice indicate an impact of VDR on intestinal homeostasis and PRRS expression.…”

“…Lack of VDR in Paneth cells can lead to viral dysregulation, which may further lead to impaired epithelial barrier function. VDR activation has a regulatory role in enterovirus-host interactions [91][92][93]. This suggests that VDR could be a potential target for study in bacterial-viral-host interactions.…”

The Role of Vitamin D in Immune System and Inflammatory Bowel Disease

“… 136 Deletion of VDR in mouse intestinal epithelial cells results in fecal dysbiosis, metabolic dysfunction, and increased risk of infection. 137 Sun et al also demonstrated that intestinal epithelial VDR knockout mice had abnormal Paneth cell function, impaired autophagy, and dysbiosis, along with downregulation of ATG16L1, a regulator of autophagy, and are susceptible to colitis. 138 In addition, intestinal epithelial VDR deficiency increases epithelial cell apoptosis and impairs cell autophagy by decreasing ATG16L1 and Beclin-1 expression.…”